Silicones in Pharmaceutical Applications. Part 2: Silicone Excipients

Silicones in Pharmaceutical Applications. Part 2: Silicone Excipients Andre Colas Jason Siang Kathy Ulman Dow Corning Corporation Midland, MI 48686

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Abstract Silicones are currently used in many different registered pharmaceutical products, both as actives (e.g. simethicones for anti-flatulent applications) and as inactives or excipients (e.g. fluids, gums and gels for topical pharmaceutical creams, ointments and lotions). Silicones are often used in these applications because of some of their unique physicochemical and performance properties, such as low surface tension, non-greasy feel, high substantivity, high permeability and controlled delivery. This article is intended to provide the reader with an understanding of where silicones have traditionally been use, or might potentially be used as excipients in pharmaceutical applications.

Kompendium (Switzerland) and AGIM® (Belgium). The search was complicated by silicone listings under compendia names (e.g. Dimethicone or Simethicone) as well as other common chemical names (e.g. silicone, siloxane, methylsiloxane, polydimethylsiloxane) and even trademarks (e.g. Silastic®). In many instances silicone (a polymer) was also confused with silicon (a metal) or silica (an inorganic compound). Some databases allowed for “word search” as in the PDR or for “list of non active substances” as in the BIAM, where others did not. The presence of silicone was found in many registered drugs, including familiar ones such as Augmentin® , Maalox ®, Prozac®, Tagamet®, Vicks VapoSteam®, just to name a few.

Introduction As the functional properties of excipients become more critical to the performance of pharmaceutical products (e.g. impact on bioavailability for drug products) the pharmaceutical industry needs to develop a good understanding of their role and select excipients based on their ability to provide intended functionality and perform throughout the intended shelf-life of the drug product. The purpose of this article is to provide a review of pharmaceutical products currently available that contain silicones, what form of silicone(s) were most often used and what attribute(s) silicones brought to the formulations.

Although it is well known that silicones are used as actives, such as Dimethicone or more often as Simethicone (a blend of Dimethicone and silicon dioxide), surprisingly, they are more often used as excipients (table 1).

Topical Formulations More than 358 registered products containing silicones were retrieved using CD Rom or internet databases such as the PDR® (USA), Rote Liste® and Gelbe Liste (Germany), MediaVidal® and BIAM (France), BNF® (UK),

While the use of silicones as “pharmaceutical actives” is well documented as antifoam in antigas or anti-acid formulations, the use of silicones as excipients is

more difficult to understand. In many cases, information about excipients is limited and it is not always possible to identify which silicones are used. However, several references indicated that silicones have been used as excipients in pharmaceutical formulations for siliconization (lubrication of syringe barrels, pistons, needles or lubrication of stoppers), as skin adhesives (drug permeable), as elastomers (drug release control membrane), as release liner coatings for transdermal patch (release coating), and, in topical skin products as polymers, volatiles/non-volatiles and as copolymers to carry actives or to improve spreading and aesthetic qualities. The latter is not surprising as silicones are widely used in Personal Care products, with around 50 % of today’s skin care products containing silicones(2) because they are recognized as safe, and known to provide for a pleasant “silky touch” non-greasy and non-staining feel. It is also worth noting that a substantial number of registered products contain silicones that are not described in any Compendia, e.g. methylpolysiloxane, silicone for powder treatment, silicone or fluo-

Table 1: Silicone occurrence as actives or excipients and physical form in registered drugs expressed as percentage of the 358 products identified in above databases(1). Silicone in composition

%

Form

%

As active

24

Simethicone Dimethicone

13 1

As excipient

70

Simethicone Simethicone emulsion Dimethicone Elastomer Silicone Oil Silicone Polymer Others

14 11 10 6 5 5 19

Unknown

6

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ro silicone for polyester film coating, silicone copolyol, hexamethyldisiloxane (HMDS), Silastic®, silicone wax, …: in these registered product formulations, the benefits brought by silicones were obviously offsetting the regulatory hurdle to file a drug formulation with a new excipient. In the above databases, 36 products (10 % of the retrieved registered products) identified silicone use as an excipient in topical products. Silicones were also declared as one of the actives in product targeted at both treatment of acne and skin ulceration prevention. The latter case may be related to the fact that NF grade Dimethicone is recognized as an OTC active for skin protectancy(3). The highest level of silicones were noted in products intended to treat skin diseases, mainly as creams followed by gels and lotions for the treatment of acne, fungal diseases or psoriasis. The non-comedogenic nature of silicone probably accounts for their use in antiacne formulations(4). Other topical applications included contact with fragile mucosa in the treatment of haemorrhoids, anal dermatoses or itch relief as well as for the delivery of antibiotics in gynecological capsules or creams. Although Dimethicones and Simethicones accounted for most of the occurrences, other specific silicones used as excipients in registered products were retrieved using the above databases: - Cyclomethicones [(Me2SiO)4, D4; (Me2SiO)5, D5; (Me2SiO)6, D6, etc], registered in Diprolene® (Schering Plough) or as decamethylpentacyclosiloxane (Me2SiO)5 in Dexeryl Crème® (Pierre Fabre Santé). Although the reason for their use is not

well known, cyclomethicones are widely used in personal care because of their volatility, “aesthetic” and safety profile; - Hexamethyldisiloxane (HMDS), where recent work(5) has shown that HMDS, Me3SiOSi Me3 (Bp. = 100°C), can be used as a volatile excipient in spray pump systems for topical applications. The low surface tension of HMDS improves skin coverage and may increases bio-availability of the active drug. One advantage of HMDS, despite its flammability, is its very low heat of vaporization, which allows a film to dry quickly; - Stearyloxytrimethylsilane, CH3(CH2)17OSiMe3, a wax with occlusive properties that provides the pleasant silky feel normally associated with silicones, is registered in Retinova® (Roc - Johnson and Johnson); - Dimethicone copolyol used in conjunction with cyclomethicones is found in Retin-A Micro® (Ortho Dermatological - Johnson and Johnson), yet the exact structure of the silicone glycol copolymer was not found in databases used. While the above silicones were certainly used as a result of their biocompatibility and probably their aesthetic benefits, emerging evidence suggests that silicones may also affect the bio-availability of actives. The substantivity of actives on the skin can be increased by adding high molecular weight silicone polymers, linear or branched, which provide better cohesion of the formed film. These substantive agents, when combined with volatile silicones such as HMDS or cyclomethicones, reduce blend viscosity and may lead to oversaturated solutions. Improved

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substantivity of cosmetic products was demonstrated using attenuated total reflectance FTIR spectroscopy, where UV sunscreen substantivity on the skin was increased in presence of PDMS gums of very high molecular weight (Mw = 700,000): the diving resistant sun cream(6) ! High molecular weight silicone gums have also been shown to improve substantivity on the skin of a pharmaceutical active, ketoprofen, when dispensed from a volatile-based silicone spray(7). After 8 hours, the presence of ketoprofen was detected on the skin surface using formulations containing a silicone gum, while it was no longer detected in the control after 6 hours. It is not clear yet if this occurred because abrasion resistance was improved or because the gum had an influence of the skin penetration rate, e.g. acting as a reservoir delaying penetration. Abrasion resistance was certainly improved: consecutive attempts, immediately after spraying, to remove the film from the skin with an adhesive tape indicated that the presence of gum made it more difficult and drug loaded films were more resistant to removal(7). Silicone gums are very substantive on their own and studies have shown that more than 25 % remains on the skin after 8 hours(8). Interesting to note is that improved substantivity was even observed when very low concentrations of silicone gum (1 to 3 % by weight) were used, thus providing a low viscosity formulation which could be easily applied by spraying and which did not unreasonably increase drying time(7). Using different actives, trials on rat skin have shown skin penetration rates and compartmental distributions between the

stratum corneum, the epidermis and the dermis were affected by the presence of silicone gum in the applied formulation; however, too few actives have been evaluated to rationalize the results (table 2 and 3). While most silicones are hydrophobic and often used to formulate lipophilic drugs, low molecular weight OH endblocked fluids, HO-(SiMe2O)n-H (n ~ 12) , have been shown to dissolve hydrophilic actives like polyethyleneoxyalkylphenols, e.g. for the preparation of spermicidal condom lubricants(9).

While polydimethylsiloxanes are highly permeable to moisture, some silicones display occlusive properties like stearyloxytrimethylsilane wax (partially silylated stearyl alcohol) and yet retain the silky touch feel usually associated with silicones (table 4). Although silicone elastomers are solids, it is possible to prepare paste like products with them when polymer crosslinking is carried out in the presence of a large concentration of a non-reactive fluid, e.g. a volatile silicone. These products can be applied to the skin in large

Table 2: Comparison of the penetration rates of different actives through hairless rat skin in Franz diffusion cells from silicone gum (2 % by weight) in silicone volatile formulations versus commercial products (without silicone)(8). Active

Cumulative amount after 24 h without silicone (µg/cm2)

Cumulative amount after 24 h with silicone (µg/cm2 )

Ibuprofen

80

180

Econazole nitrate

0.7

0.5

Hydrocortisone

0.4

0.4

Table 3: Comparison of the compartimental distribution in hairless rat skin of different actives after 24 h from silicone gum (2 % by weight) in silicone volatile formulations versus commercial products (without silicone)(8). Active

Ibuprofen

Drug distribution for formulations w/o silicone (% of initial drug load) str.corn. epidermis dermis 1 0.2 0.3

Drug distribution for formulations w silicone (% of initial drug load) str.corn. Epidermis dermis 1 0.2 1.5

Econazole nitrate

3.5

1

1

4

1

1

Hydrocortisone

0.2

2.5

0.5

7

2

0.8

Table 4: Comparison of oil-in-water emulsion occlusivity of Vaseline and/or stea ryloxytrimethylsilane wax via gravimetric water loss through gelatin membranes using the following formulations: oily ingredient: 20 %; silicone glycol copolymer emulsifier: 2 %; HMDS 10 %; EtOH: 10 %; water + 2 % NaCl: qsp(8).

Oily ingredient

Occlusivity Power (%)

Vaseline emulsion

93.4

Vaseline / silicone wax 50 - 50 emulsion

84.7

Silicone wax emulsion

72.9

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quantities while maintaining an exceptional feel. They are widely used in Personal Care products and it has recently been shown that they can be used as carrier for the release of actives(9). Conclusions Silicones have a history of more than 50 years of safety and efficiency in health care related applications and polydimethylsiloxanes are globally recognized both for their proven biocompatibility as well as for being one of the most tested materials for their safety. As excipients, many of the unique properties of PDMS have been exploited in controlled release drug delivery systems due to their: chemical stability, high level of purity (absence of organic solvent or heavy metal contamination; low level of residual polydimethylcyclosiloxanes), ease of use to manufacture different designs and very high permeability to many active drugs. Because of their unique physicochemical properties, silicones are especially suitable for providing aesthetics and bioavailability of actives for topical formulations. Note: Parts of this article were originally published in Chimie Nouvelle, 15 (58), 1779 (1997) by A. Colas and L. Aguadisch of Dow Corning Europe and is reproduced here with the permission of the Editor.

References 1. A. Colas, “Silicones Polymers and Elastomers as Excipients in Pharmaceuticals”, Belg. Plast. Rub. Inst. conference,‘t Gravenends, Belgium (2000). 2. M. Delvaux, private communication (2001) 3. United States Food and Drug Administration Skin Protectant Drug Products for Over-theCounter Human Use; Final Monograph, 21 CFR 347. 4. C. E. Creamer, Pharm. Technol., 6 (3), 79 (1982). 5. J.M. Aiache, Aerosol and SprayReport, 35 (4), 190 (1996). 6. G. Chandra and H. Klimisch, J. Soc. Cosmet. Chem., 37 (2), 73 (1986) 7. L. Aguadisch and coll., EP 0 966 972 (1999) 8. C Mallard and L. Aguadisch, Interchimie (1999). 9. A. Etienne and L. Aguadisch, EP 0 475 664 (1992)

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